Neuroprosthetic devices have the potential to restore functionality to patients with sensory loss, spinal cord injuries, and certain neurological diseases that affect brain function and signaling to the body. One major issue preventing the development of effective long-term neuroprosthetic devices is the lack of electrodes that function for long periods of time in the biological environment. Currently, chronically implanted electrodes evoke an immune response from surrounding tissue which promotes inflammation and scar formation, presenting a barrier that can block electrical signal transfer between neurons and the electrode. This blockade prevents signals from reaching the electrode surface, rendering the device useless. We are engineering non-fouling microgel coatings for neural electrodes that contain enzyme-cleavable sequences (ECS) to release anti-inflammatory agents (AIA) in an on-demand fashion in response to inflammation in the surrounding tissue environment. The AIAs will serve to reduce inflammation and subsequent scar formation that occurs in the area surrounding the electrode. By mediating scar formation, we hypothesize that electrical signal communication between neurons and electrode can be maintained, extending the lifetime of the device in vivo. This research will be beneficial for applications involving monitoring of electrical signals in the brain, as well as applications where stimulation is provided by the electrode to surrounding neurons. In order to develop an effective electrode that can maintain functionality for long-term use, we will incorporate ECS with tethered AIAs into the microgel system. These ECS will incorporate a stimulus-dependent response to increases in thrombin, MMP-9, and MMP-2, which are present in short-, mid-, and long-term inflammation. The on-demand response of the ECS is innovative because it allows for controlled release of the AIAs in response to the amount of inflammation that is present in the surrounding area. AIA trials will include corticosteroids, proteins, and small molecules. Each ECS will be combined with each AIA, and all iterations will be tested in a 3D co-culture system that includes microglia, astrocytes, and neurons. The best performing combinations of ECS and AIA will then be tested in an in vivo rat model and compared to uncoated electrode data analyzed using immunohistochemical analysis and neural recordings to demonstrate the increased effectiveness of the microgel coatings for reducing scar formation around chronically implanted neural electrodes. PUBLIC HEALTH RELEVANCE: This project is important for improving public health because the research conducted as part of this proposal will help to improve the functionality of neural electrodes that are implanted in the brain for long periods of time. The new polymer coatings applied to these neural electrodes will utilize an on-demand response to mediate the inflammation that occurs after implantation and allow electrodes to receive electrical (neural) signals for longer periods of time than with standard uncoated electrodes.